FR2773320A1 - DEVICE FOR THE INTRAOCULAR TRANSFER OF IONTOPHORESIS ACTIVE PRODUCTS - Google Patents

Abstract

The instrument for the transfer of an active ingredient e.g. a medication into the eyeball, by iontophoresis, has a reservoir (15) for the medication which can be applied to the patient's eye. The reservoir has at least one active surface electrode (11) opposite an ocular tissue, at the periphery of the cornea (C). It also has a return electrode (12) and an electrical current generator. The return electrode is preferably in contact with the patient's closed eyelids (22,24). The reservoir has a number of compartments as ring segments, for different medications, each with its own active electrode.

Description

DEVICE FOR INTRAOCULAR TRANSFER

OF ACTIVE PRODUCTS BY IONTOPHORESE

  The present invention relates to a device for intraocular transfer of active products by iontophoresis. Iontophoresis is a technique that was proposed as early as 1747 by VERRATI and which consists of the administration of drugs in the body through the tissues using an electric field involving a small difference in potential. The active electrode, which is in contact with the

  drug is disposed at the place to be treated while a second electrode for closing the electrical circuit is placed at another location on the body.

  The electric field facilitates the migration of preferably ionized active products. This technique is commonly used for the treatment of dermatological diseases and there are different devices available for this purpose.20 The iontophoresis applied to the treatment of the eye has been the subject of many animal experiments and some tests clinics, using

different devices.

  Known devices employ a tampon soaked in a solution containing a drug, and which is in contact with the surface of the cornea and the sclera. Other devices use a cup or a pipette. A device implementing a

  cupule is, for example, described in the US Pat.

  United States 4,564,016 (David M. MAURICE). In this one, the administration of the drug is carried out in a

  almost punctual across the sclera.

  In general, the authors note a poor reproducibility of their results, which they attribute either to the existence of differences between the animals tested, or to unexplained biological phenomena. In addition, certain operating techniques involve the use of a very small surface active electrode with a very high current density which increases the risk of damage to tissue, which can include burns. This is the case in particular of the device

  described in the aforementioned US Pat. No. 4,564,016 which recommends a current density of at least 50 mA / cm 2 and can even reach 2000 mA / cm.

  Some experiments have been carried out with alkaline solutions whose high pH results in local tissue damage. For example, the article by T.T. LAM and Collaborators "Intravitreal Delivery of Ganciclovir in Rabbits by Transscleral Iontophoresis" published in the Journal of Ocular Pharmacology 10 (3) p. 571-575 (1994), describes the point administration of a solution whose pH of

  , 8 is not possible outside the laboratory.

  The article by F. BEHAR-COHEN and Collaborators, entitled "Iontophoresis of Dexamethasone in the Treatment of Endotoxin-Induced-Uveitis in Rats" published in the Review Experimental Eye Research, 1997-65 p. 533-545 (Oct. 1997), relates to transcoreosclerotic iontophoresis performed

  in rats, for the treatment of uveitis, that is,

  to say a pathology affecting the uvea. According to this technique, the diffusion of the drug proceeds essentially through the cornea and then diffuses into

ocular media.

  In practice, the lack of reproducibility of the experimental results generally obtained and especially

  the description of burns and tissue necrosis on

  application site of the iontophoresis devices, resulted in transocular iontophoresis remaining at the laboratory stage and still not

  recognized as a method of treating patients.

  The subject of the invention is a device for transferring at least one active product into the eyeball by iontophoresis, which makes it possible to carry out

  ambulatory treatments in a reproducible manner.

  The invention thus relates to a device for transferring at least one active product into the human eyeball by iontophoresis comprising a reservoir of active product, for example a drug, which can be applied to the eye of a patient, at the less an active electrode disposed in the reservoir, a passive electrode and a current generator, characterized in that said active electrode is a surface electrode disposed opposite ocular tissues located at the periphery of the cornea. The regions of the eyeball facing the electrode are the corneoscleral limbus, the conjunctiva and / or the sclera and / or the ciliary body and / or the root of the iris and / or the parsplana and / or the anterior vitreous, and / or the retina

non detachable non-functional.

  Since the transfer takes place through one or more ocular tissues located on the periphery of the cornea over a large area of application, reproducibility, homogeneity of transfer and efficiency are increased. These tissues are imbued with the drug (or active product) that can even concentrate there while the concentrations in the ocular media remain low. These concentrations do not reflect intratissue drug concentrations. The drug is not eliminated quickly by the renewal of eye fluids

(AH aqueous humor and vitreous V).

  On the other hand, since the active product is not in contact with the cornea, it avoids the disadvantages of transcorneal iontophoresis and the risk of endothelial lesions, namely the existence after the intervention of disorders of the related to either endothelial lesions, transient epithelial lesions, or transient deposition of active products, resulting in blurred vision. As a result, the treatment is truly ambulatory. Finally, since the treatment is carried out on a crown peripheral to the cornea, a cylindrical central region of the device can be completely disengaged and thus the practitioner can visually control the central positioning of the device during iontophoresis. All ocular tissues can be treated: conjunctiva, cornea, sclera, iris, crystalline,

  ciliary body, choroid, retina, optic nerve.

  Depending on the parameters chosen for the current (intensity of current, duration of treatment),

  some tissues may be more specifically targeted.

  For an adult (nominal diameter of the cornea: 12 mm), the annular electrode or the electrodes in the form of annular sectors, made for example by electrodeposition, may have an internal diameter of between 12.5 mm. and 14 mm and an outside diameter of between 17 mm and 22 mm, which corresponds to

2 2

  at an area of between about 75 mm2 and 250 mm2, and preferably between 17 mm and 20 mm. The maximum diameter is chosen so as not to reach the functional retina. For a child whose eye has not reached the adult size, it is necessary to adapt the dimensions in proportion. In other words, and in the general case, the inner diameter di of the annular electrode or electrodes is greater than the diameter D of the cornea and less than or equal to 1.2D, and the outer diameter of the annular electrode or electrodes is greater than or equal to 1.4D and less than or equal to 1.8D, and preferably

less than or equal to 1.7D.

  The current generator may be a constant current generator with a nominal density of less than 10 mA / cm 2 which includes a control device for applying said constant current for a period of time for example between 30 seconds and 10 minutes and more particularly between 1 minute. and

minutes.

  The density of the constant current is advantageously adjustable between 0.1 mA / cm 2 and 5 mA / cm 2, for example between 0.2 mA / cm 2 and 5 mA / cm 2 or between 0.8 mA / cm 2

and 5mA / cm2.

  The application of the current can be carried out in a progressive manner, for example during the first seconds, which avoids the reflex muscular reactions

of the patient.

  The current is advantageously supplied at a voltage of between 1.5V and 9V and preferably between

2V and 8V.

  The concentration of the active product can be any. In particular, it is less than or equal to the saturation concentration of the active product in water. It is preferably greater than or equal to a threshold concentration from which accumulation occurs in certain tissues of the eye followed

  release to other tissues.

  The active product disposed in the reservoir has a pH which may advantageously be between 6 and 8 and preferably between 7 and 7.6. It should be noted that since the active product is not in contact with the cornea, the pH chosen may be substantially higher than indicated above, because the conjunctiva and the sclera are less sensitive both sensitively and experimentally at pH. a little acidic or basic. The cornea must remain transparent. Any change in physiological conditions may alter its tissue characteristics, hence its transparency. The conjunctiva is a mucous membrane, the saw bone is a connective tissue. They are two very resistant tissues and whose function is not, in the region of application of the treatment, directly involved in the transmission of photons towards the retina. These are supportive fabrics. The device preferably has a pumping device for circulating a solution of active product, for example a drug solution, in the reservoir. This makes it possible, on the one hand, to eliminate the gas bubbles that may form during iontophoresis, and on the other hand to keep the composition and the pH of the solution substantially constant for the duration of the period of time.

  treatment and therefore improve its reproducibility.

  According to a first embodiment, the device has an annular reservoir having an annular electrode, which can delimit the bottom of the tank. According to a second embodiment, the device has an annular reservoir having a plurality of compartments in the form of annular sectors and annular sector-shaped electrodes, which can delimit the bottom of the sectors.

ring.

  According to a third embodiment, the device is constituted by a corneal lens provided on its inner face with a surface electrode and in which is disposed a gel containing at least one active product, or which itself is spongy in structure and contains the active product, (for example a

crosslinked matrix).

  Preferably, the device comprises on an outer face a passive electrode which comes into contact with the patient's partially closed eyelid, which holds the device in place during the treatment period. This also provides the advantage

  an improved electrical contact, because in an aqueous medium.

  Other features and advantages of the invention will appear better on reading the

  description which will follow, given as an example not

  limited in connection with the accompanying drawings in which: - Figures la and lb respectively represent in section and in top view an example of

  described in the aforementioned article by F. BEHAR-

  COHEN et al. FIGS. 2a and 2b show respectively in section and in plan view an exemplary device according to the invention; FIGS. 3a, 3b and 3c respectively represent in section, in plan view and in perspective, a device according to the invention allowing the administration of three active products, for example three drugs FIG. 4 represents in section a variant of the device according to FIGS. 3a to 3c; FIGS. 5a and 5b show a device according to the invention, in the form of a meniscus intended for the administration of three active products, for example three drugs, in the form of a gel - FIGS. 6a to 6c show respectively in perspective, in section, and in partial section a device of the meniscus type according to the invention - FIG. preferred embodiment of a device for the administration of several active products, for example drugs - FIGS. 8a and 8b are results of an effect test in rabbits, with ordinate the concentration in pg / mg of dry tissue and in pg / ml for ocular media, and abscissa time in hours and Figure 9 shows a device according to the invention as set up on an eye to treat. FIG. 1 diagrammatically represents the iontophoresis system implemented in the context of the aforementioned article by F. BEHAR-COHEN et al. It comprises a tank 8 made of polymethylmethacrylate (PMMA) delimited by a cylindrical wall 2 and a bottom 3 near which is disposed a circular electrode 4 platinum. The reservoir 8 of diameter 6 mm covers the cornea, the limb and the first millimeter of the sclera of a rat. A feed tube 5 makes it possible to fill the reservoir 8 with a solution dosed at the rate of 1 mg of Dexamethasone per ml of a sterile saline solution of pH 7, and an evacuation tube 6 makes it possible to extract the

  air bubbles that form during iontophoresis.

  A continuous circulation of the solution makes it possible to maintain constant the pH of the solution in contact with

the cornea.

  A return electrode 7 is placed in

contact with a rat's paw.

  The system also comprises a voltage source VS, and a current regulator I. An impedance measurement device IMM makes it possible to detect any electrical discontinuity and to trigger an alarm A. The quantity of charges delivered is displayed on the generator at the end. treatment and ensures the

  reproducibility of the treatment administered.

  The experiments were carried out with a current of 400pA for 4 minutes, a density of 1.2mA / cm 2 and a total charge of 0.12 Coulombs or 0.4C / cm 2. The device according to the invention, an embodiment of which is shown in FIGS. 2a and 2b, 9 enables a transfer of active product, for example a drug, essentially through at least one ocular tissue. The active electrode is advantageously placed at a distance a from the surface of the patient's eye which is sufficient to avoid a short circuit, or to prevent it from being accidentally in contact with the eye. This distance a is preferably at least

equal to 4 mm.

  The device may be made of PMMA or preferably of silicone, for example PDMS of hardness Shore 20, for a better sealing at the level of the eye. The device 10 has an annular wall 17 and two cylindrical inner and outer cylindrical walls 19 delimiting an annular region 15 forming a reservoir for an active solution, for example a medicinal solution, to be administered by iontophoresis to the

  periphery of the cornea C of an eye to be treated 20.

  The end of the wall 18 opposite the wall 17 rests with a frustoconical flange 16 on the sclera S and the end of the wall 19 opposite the wall 17 rests with a frustoconical zone 19 'around the perimeter of the cornea C of in such a way that only a region peripheral to the cornea C and having one or more ocular tissues is bathed in the medicinal solution contained in the reservoir 15. An annular active electrode 11 borders the wall 17. Two conductive links 11 'and 12' make it possible to connect electrically the active electrode 11 and the return electrode 12, which is advantageously disposed on the outer face of a ring 16, so that the partially closed eyelid of the patient can come into contact with the electrode 12 and thus close the circuit. o10 Alternatively, the return electrode can

  be separated and placed on the patient's forehead in the vicinity of the eye to be treated.

  Openings 13 and 14 formed in the wall 17 allow a filling of the tank 15 and / or a

  circulation of the drug solution.

  The flat annular electrode 11 preferably covers the entire surface of the wall 17 which defines the bottom of the annular reservoir 15. A partial recovery only is possible, but it can affect only adversely the effectiveness of the treatment. In any case, the reservoir 15 must not cover a region of the cornea C.15 The device shown in FIGS. 3a, 3b and 3c allows the administration of several active products, for example medicaments, here 3, in the form of liquid or gel which are each arranged in one of three annular sector shaped cavities 45, 46 and 47 each provided with an active electrode respectively 41, 42 and 43. The device comprises an annular wall 27, and two inner cylindrical walls 49 and 48, and the sectors are delimited by partition walls 40. It is placed on the patient's eye in the same way as the device shown in Figures 2a and 2b. Conductive connections 41 ', 42' and 43 'pass through the wall 27 to electrically supply the electrodes

active 41, 42 and 43.

  The device shown in FIG. 4 is distinguished by the presence of liquid circulation tubes which are present for each cavity 45, 46 and 47. In the drawing, the tubes 84, 85 and 86, 87 are visible.

  corresponding to cavities 45 and 46.

  The device shown in Figures 5a and 5b is a meniscus shaped crown. It has three reservoirs 55, 56 and 57, each of which is intended to receive a medicinal gel or a porous material, such as a sponge, impregnated with an active product, for example a medicament. Each reservoir is associated with an active electrode 51, 52 and 53 respectively. The sector-shaped reservoirs 55 are delimited by

dividing walls 50.

  The device represented in FIGS. 6a to 6c is a flat meniscus in the form of a crown made in a

  material that can be that of a corneal lens.

  The central cylindrical space 63 is clear and allows, as with the other embodiments, a visual control of the centric positioning of the device. An electrode 61, for example formed by electroplating, covers the slightly concave internal face 63 of the bottom of the annular cavity 62. A return electrode 64, for example formed by electroplating, covers the periphery of the convex outer face 66 of the cavity bottom. annular 62, so as to allow electrical contact back by at least one of the closed eyelids 22, 24 of the patient. The passage of the electrical contact wires 67, 68 is arranged so as to allow their

exit between the eyelids.

  The device according to the invention is generally suitable for single molecules or molecular assemblies used as active product (for example medicaments and / or peptides and / or proteins and / or gene fragments) and whose mass

  molecular weight is less than 100 kilodaltons.

  We operate with direct current, constant and regulated

  with a current density not exceeding 10mA / cm2.

  This current density is advantageously adjustable

2 2 2

  between 0.1mA / cm and 5mA / cm 2, and for example between 0.2mA / cm and 5mA / cm 2. Preferred value range is included

2 2

  between 0.8mA / cm and 5mA / cm2. The treatment time can be between 30 seconds and 10 minutes. It can in particular be between 1 minute and 10 minutes. For the human being, the diameter of the cornea (with limb) is about 12 to 13 mm with an ora serrata about 18 mm in diameter. By way of example, an annular electrode or a plurality of ring sector electrodes having an internal diameter of between 12.5 and 14 mm and an external diameter of between 17 mm and 22 mm can be used for the treatment of adults, which

2 2

  corresponds to an area of between 75 nm 2 and 250 mm, and preferably between 17 mm and 20 mm. The current can be in this case for example 400uA and be

applied for 4 minutes.

  It will be noted that the arrangement of the active electrodes, namely surface electrodes arranged opposite the region (s) to be treated makes it possible to associate with a constant current a current density which is itself constant and homogeneous over any

  the surface of the region to be treated.

This has several advantages.

  In the first place, it is avoided that the current density can locally reach high values in certain areas of the region to be treated and therefore

  to be the cause of undesirable side effects.

  On the other hand, the homogeneity of the current density in the region to be treated has the effect that the penetration of the active product (s), for example drugs, is also homogeneous over the region to be treated.

treat.

  In no case, the electrode is vis-à-vis

functional retina.

  In the context of the present invention, the administration of at least one active product, for example a drug, is carried out via the tissues that allow the best penetration of the active product, 13 in the anterior and posterior segment: the limbus

  corneoscleral, conjunctiva, sclera, ciliary body, iris root, parsplana, vitreous anterior, choroid, and non-releasable non-functional retina.

  The absence of contact with the cornea avoids any risk of physical and chemical injury and in particular transient or permanent eye disorders consecutive treatment, and it also allows to clear a central space allowing the practitioner to control the positioning of the device during all the treatment. In addition, it can be seen that starting from a certain concentration of active product, which varies according to the nature of the active product, the active product

  accumulates in certain tissues of the eye (sub-space

  tenon, sclera, suprachoroidal space and to a lesser extent iris I and ciliary body CC) before being progressively released to other tissues (choroidal CH, RET retina), thus increasing the duration of action

  (half-life time before removal of the active product).

  This phenomenon is illustrated by the curves below.

  attached (Fig. 8a and 8b), obtained from experiments on rabbits with methylprednisolone hemisuccinate (150 mg / ml, 2mA). With a 62.5 mg / ml solution, the salting out effect is not observed. The concentration threshold allowing a release is

about 1001 mg / ml.

  The device according to the invention may be of revolution, but it is preferable that it be substantially oval to take account, on the one hand, of the presence of the eyelids and, on the other hand, of the profile.

slightly oval of the cornea.

  The device represented in FIG. 7 has a cavity having an elliptical external profile of mm of focal axis parallel to the closure line of

  eyelids, and 18 mm of minor axis.

  An elliptical internal profile of the treatment cavity may for example have a major axis parallel to the closure line of the eyelids and equal to 13.5 mm, and a small axis perpendicular to this line and

equal to 12.5 mm.

  The device shown in FIG. 7 has four cavities 71 to 74, each of which has an active electrode 75 to 78 fed by an individual electronic circuit 79 to 82 similar to that shown in FIG. 1 and which is integrated in the device. The electronic circuits are powered by a battery 84 constituting the voltage generator VS, and comprise a constant current source I regulated to a chosen value, and a timer T to set the desired treatment time. Alternatively, all the circuits can be arranged on a single integrated circuit, or even the functions can be distributed over several internal circuits connected by a

bus 85.

  Note that the tank may be oval or have an elongate shape, for example elliptical. The reservoir and / or the active electrode can

to be annular.

  It is also within the scope of the present invention that the reservoir has an internal diameter di with D <di <1, 2D, D denoting the diameter of the cornea, and an external diameter of, with 1.4D <of <1, 8D, and preferably 1.4D <1 <7D.

Claims (16)

  1. Device for transferring at least one active product into the eyeball by iontophoresis, comprising a reservoir of active product, and capable of being applied to the eye of a patient, at least one active electrode disposed in the reservoir , a passive electrode and a current generator, characterized in that one said active electrode is a surface electrode (11,41,42,43,51,52,53,61) disposed facing at least one ocular tissue located at the periphery of the cornea.   2. Device according to claim 1 characterized in that the current generator is a constant current generator of nominal density less than 10 mA / cm 2, and in that it comprises a control device for applying said constant current during a duration between 30 seconds and 10 minutes, and especially between 1 minute and 10 minutes. 3. Device according to claim 2 characterized in that said current density is 2 2 between 0.1mA / cm and 5mA / cm.   4. Device according to claim 3 characterized in that said current density is 2 2   between 0.2mA / cm and 5mA / cm2, and especially between 2 2 0.8mrA / cm and 5mA / cm2.   5. Device according to one of the claims   characterized in that the reservoir (15,45,46, 47,55,56,57) and / or the active electrode (11,41,42,43,51, 52,53) is annular.   6. Device according to one of the claims   characterized in that the reservoir (15,45,46, 47,55,56,57,71,72,73,74,62) has an internal diameter di with D <di <1,2D, D denoting the diameter of the cornea, and an outer diameter of with   1.4D <<1.8D, and preferably 1.4D <1.7D.   7. Device according to claim 6 characterized in that the internal diameter di is between 12.5 mm and 14 mm and in that the outer diameter of is between 17 mm and 22 mm and preferably between 17 mm and 20 mm .   8. Device according to one of the claims   characterized in that said current is supplied at a voltage of between 1.5V and 9V and especially between 2V and 8V.   9. Device according to one of the claims   characterized in that said active product disposed in the reservoir (15,45,46,47,55,56,57,71,72, 73,74,62) has a pH of between 6 and 8 and preferably between 7 and 7.6.   10. Device according to one of the claims   previous characterized in that it comprises a pumping device for ensuring a flow of a drug solution in the tank.   11. Device according to one of the claims   characterized in that the device has an annular reservoir having a plurality of compartments (45,46,47,55,56,57, 71,72,73,74) in the form of annular sectors and electrodes (41,42 , 43.51, 52.53,   75,76,77,78) in the form of annular sectors.   Device according to one of the claims   characterized in that the device has an annular reservoir having a compartment (15,62).   and an annular electrode (11,61).   13. Device according to one of the claims   characterized in that the reservoir (15,45,46, 47,55,56,57) has an elongated shape elliptical example.   14. Device according to one of the claims   characterized in that the reservoir (45,46,47,55,56,57,62) contains at least one gel or a porous material such as a sponge impregnated with a product   active. 15. Device according to one of the claims 11   at 14 characterized in that the device is a flat meniscus.   16. Device according to one of the preceding claims characterized in that it comprises on one side   external a passive electrode (12,44,64) which comes into contact with the inner face of the patient's at least partially closed eyelid, which holds the device in place for the duration of the treatment.